TY  - JOUR
A1  - Schmidl, Sina
A1  - Ursu, Oleg
A1  - Iancu, Cristina V.
A1  - Oreb, Igor-Mislav
A1  - Oprea, Tudor I.
A1  - Choe, Jun‑yong
T1  - Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
T2  - Scientific reports
N2  - Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi–Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.
KW  - Drug discovery and development
KW  - Membrane proteins
KW  - Virtual screening
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63258
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-632582
SN  - 2045-2322
N1  - This work was supported by NIH Grant R01-GM123103 (to M.O., T.O., J.C.).
VL  - 11.2021
IS  - art. 13751
SP  - 1
EP  - 12
PB  - Springer Nature
CY  - London
ER  -